This application addresses broad Challenge Area (15): Translational Science and specific Challenge Topic, 15- DK-103: Translate discovery of new molecules and pathways in pathogenesis of NIDDK diseases into potential therapies, diagnostics, or research tools. Polycystic kidney disease is one of the most common human genetic diseases and a major cause of chronic renal insufficiency requiring dialysis or kidney transplantation. There is compelling evidence that in autosomal dominant polycystic kidney disease (ADPKD) progressive fluid accumulation into cysts requires chloride secretion by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a cAMP-regulated chloride channel, which, when mutated, causes the genetic disease cystic fibrosis. Cyst growth in ADPKD requires fluid secretion into the cyst lumen coupled with epithelial cell hyperplasia. CFTR inhibitor 'antisecretory therapy'may offer life-long therapy to prolong kidney survival in ADPKD. At present there is no FDA-approved drug to prolong kidney survival in ADPKD. Our laboratory has identified, by high-throughput screening, two classes of small-molecule CFTR inhibitors, thiazolidinones and glycine hydrazides, which, in published proof-of-concept studies, are effective in preventing cyst fluid accumulation in ADPKD models. A large screen recently yielded a third class of pyrimido-pyrrolo-quinoxaline (PPQ) CFTR inhibitors that have unique properties and are very potent and effective in preventing cyst expansion in kidney organ culture models. The first aim of this application is to select, using kidney organ culture and pkd1 knockout mouse models, the best small-molecule CFTR inhibitors for preventing cyst growth in ADPKD. CFTR inhibitors of the thiazolidinone, glycine hydrazide and PPQ classes will be evaluated. The goal of this aim will be to select the best inhibitor(s) of each class that are effective in preventing cyst growth, non-toxic, and orally bioavailable. The second aim will be to prioritize the best CFTR inhibitors selected in the first aim, based on analyses of pharmacokinetics, ADME (absorption, distribution, metabolism, excretion), toxicity and mutagenic potential. The goal is to select the best one or two compounds for further pre-clinical development. PUBLIC HEALTH RELEVANCE: Polycystic kidney disease is one of the most common genetic diseases and a major cause of kidney failure leading to dialysis or kidney transplantation. New drug candidates, called CFTR inhibitors, discovered by our laboratory will be tested for their potential in treating polycystic kidney disease using culture and animal models. This new form of therapy might ultimately prolong kidney function in polycystic kidney disease.